Glucagon is a key hormone in the regulation of glucose homeostasis. Probably its most important site of action is the liver where it stimulates glycogenolysis and gluconeogenesis. Glucagon action appears to be initiated by attachment of glucagon to a specific cell surface receptor which is in some way coupled to membrane-bound adenylate cyclase. Adenylate cyclase is the key enzyme involved in cyclic-AMP production. In several hepatomas induced by carcinogens, there is a loss of adenylate cyclase response to glucagon. One of the main objectives of this project is to elucidate the mechanism of loss of the glucagon-induced adenylate cyclase response in various hepatomas. Is there actual loss of the glucagon receptor or is there masking of the receptor? Or possibly is the defect not in the receptor but in coupling (or transduction) of the receptor to adenylate cyclase.